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Modular Assembly of Furotropones and Benzofurotropones, and Study of Their Physicochemical Properties Rajendra P. Shirke and S. S. V. Ramasastry* Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Sector 81, SAS Nagar, Manuali, Punjab 140 306, India S Supporting Information *

ABSTRACT: A rapid and straightforward synthesis of a novel series of furo[2,3-d]tropones (or cyclohepta[b]furan-6-ones) has been developed starting from readily and commercially available materials. Directed α-lithiation of furan-3-carboxaldehydes and subsequent reaction with a variety of aldehydes efficiently provide, in one step, access to 3-formyl-2furylcarbinols, which are otherwise only accessible with difficulty. The 3-formyl-2-furylcarbinols are further elaborated in two steps to the synthesis of furo[2,3-d]tropones in good yields via sequential bismuth(III)chloride-catalyzed furfurylation and an unusual base promoted cyclization strategy. Thus, diverse polysubstituted furotropones and benzofurotropones can be rapidly assembled. This methodology thereby offers a potential approach for the synthesis of several bioactive natural products containing cyclohepta[b]furan core and also for the buildup of complex molecular architectures through higher order cycloaddition reactions of tropones. Further, the new chromophores have been found to possess promising fluorescence properties. Selective fluorogenic sensing behavior of furotropones toward Fe3+ ions has also been elucidated.

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INTRODUCTION Among nonbenzenoid aromatics, tropones have been studied in great detail from synthetic and theoretical standpoint.1 Occurrence of several troponoid natural products possessing interesting biological activities spurred several studies directed toward understanding structure activity relationships as well as their physicochemical properties.2 Tropones traditionally have been employed in several higher order cycloaddition reactions3 and quite often as synthons in natural product synthesis.4 Among annulated tropone derivatives, aryl-annulated tropones are well-studied, while heteroaryl-annulated tropones are mostly unfamiliar.5 A detailed literature review exposes lack of synthetically flexible methods for the synthesis of heteroarylannulated tropones and also a general understanding about their physical and biological properties is particularly missing. Toward this, we have initiated research to establish a short, efficient and scalable approach for the synthesis of previously unknown furo[2,3-d]tropones from readily available starting materials. Known methods for the synthesis of furo[2,3d]tropones are depicted in Scheme 1.6 The key step in El-Borai and Shafiee’s approach (method-1, Scheme 1) for tropones involved the cyclocondensation of furan or benzofuran-2,3dicarboxaldehydes I and ketones II under strong basic conditions.6a,b On the other hand, Takeshita’s Claisen rearrangement of (E/Z)-4-(3-chloro-2-propenyloxy)tropones III under thermal conditions furnished furo[2,3-d]tropones (method-2, Scheme 1).6c Evidently, these methods are associated with the drawbacks such as (i) difficult-to-access © XXXX American Chemical Society

starting compounds, (ii) harsh reaction conditions, (iii) poor yields, (iv) limited substrate scope (that hinders diversification). Herein we describe general synthesis of a variety of furoand benzofuro[2,3-d]tropones, study of their physicochemical properties, and especially their ability in cation sensing.

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RESULTS AND DISCUSSION Synthesis and Characterization of Tropones. A general approach toward the synthesis of furotropones is depicted in Scheme 2. To begin with, commercially available 3furancarboxaldehydes of the type A are converted to 3formyl-2-furylcarbinols B in a single step via regioselective directed α-lithiation-alkylation strategy published earlier by our research group.7 Following this strategy, aldehyde functionality in 3-furancarboxaldehydes A can be masked by treatment with lithium N-methylpiperazide [LNMP, obtained by the reaction of N-methylpiperazine (NMP) and n-BuLi]. Chelation controlled lithiation of the resulting adduct at the C-2 position with n-BuLi generates 2-lithiofurans in highly selective manner. Reaction of 2-lithiofurans with aldehydes (or ketones) and subsequent hydrolysis generates conveniently 3-formyl-2furylcarbinols B. Bismuth(III) catalyzed reaction of furylcarbinols B and 1,3-dicarbonyls C generate the tricarbonyls D in very good yields via intermolecular Friedel−Crafts-type reaction.8 Base mediated intramolecular aldol condensation of Received: January 31, 2015

A

DOI: 10.1021/acs.joc.5b00226 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 1. Known Methods for the Synthesis of Furo[2,3-d]tropones

Scheme 2. One-Step Synthesis of 3-Formyl-2-furyl Carbinols (B) and a Two-Step Synthesis of Furotropones and Benzofurotropones (E)

diketoaldehydes D delivers furotropones E in good to excellent yields via cyclization of the dienolates F on to the appropriately positioned aldehyde functionality and subsequent aerobic oxidative aromatization of G.7 This method thus constitutes a general, short, efficient and straightforward approach for the synthesis of cyclohepta[b]furan-6-ones (commonly referred to as furotropones). Some advantages of furan-based strategies are the ready availability of starting materials, ease of manipulation and high degree of synthetic flexibility. Since the general synthetic approach described in Scheme 2 permits diversity across the aldehydes A and H, and the dicarbonyls C, a variety of highly functionalized furotropones and benzofurotropones (3a−3n) could be rapidly synthesized, Table 1. All the new compounds were fully characterized by comprehensive spectroscopic data. All of these heteroarylannulated tropones exhibited good solubility profiles in common organic solvents such as toluene, DCM, THF,

DMSO, DMF, ethanol, ACN, etc., at room temperature itself. Most of the tropones were isolated as colorless to pale yellow solids. Tropones possessing both aliphatic and aromatic β-ketone functionality (at C-7) could be accessed efficiently via this methodology (Table 1, entries 1−9), in addition to a diverse range of aryls and heteroaryls at C-8. More interestingly, tropones with β,β′-diketones are of particular interest from synthesis point of view (Table 1, entries 10−12). This novel class of tropones can be accessed by the reaction of triketones such as 2d and 3-formyl-2-furylcarbinols under standard conditions. This methodology is found to be particularly efficient in establishing a short and scalable method for the synthesis of new benzofurotropones in good yields (Table 1, entries 13 and 14). By virtue of the inherent restrictions the mechanism involves, there exist certain structural limitations for 1,3-dicarbonyls. For B

DOI: 10.1021/acs.joc.5b00226 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

Table 1. Scope of Various Aldehydes and 1,3-Dicarbonyls for the Synthesis of a Variety of Furotropones and Benzofurotropones

generate tropones. Indeed we prepared respective tricarbonyls with the general structure D with aforementioned dicarbonyls, attempted base mediated intramolecular aldol reaction was unsuccessful and yielded no meaningful product. In addition, step-III failed to deliver tropones in cases where R1 is aliphatic. Interestingly, reaction of 3-formyl-2-furylcarbinols 3a1 and 3c1, and 3-methylpentane-2,4-dione 2e under bismuth(III)

example, cyclic diketones (such as 1,3-cyclohexanedione 2f or the β-ketoester 2g) cannot form tropones obviously because of the inaccessibility of dienolate intermediates toward the aldehydic carbonyl, even otherwise also would lead to highly energetic bridged structures. Likewise, the diketones of the type 1,3-diphenyl-1,3-propanedione 2h (not possessing α-acidic protons and thus dienolate formation is hindered) or 2i cannot C

DOI: 10.1021/acs.joc.5b00226 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 3. Synthesis of C-7 and C-8 Disubstituted Furotropones via Retro-Claisen Condensation

Scheme 4. Synthesis of Mono (C-8) Substituted Furotropones via in Situ Ethoxy Decarbonylation

Scheme 5. Synthesis of 2,3′-Bifuran Derivatives

catalysis generated expectedly the diketoaldehyde 3o2 and 3p2. Reaction of 3o2 and 3p2 under base mediated reaction furnished, surprisingly, 7,8-disubstituted furotropones 3o and 3p, respectively, in good yields, presumably via a retro-Claisenaromatization sequence as shown in Scheme 3. After the initial aldol condensation, in order to attain aromaticity, the 7,7,8trisubstituted cyclohepta[b]furan-6-ones 3o3 and 3p3 undergo base-mediated retro-Claisen cleavage followed by aromatization to form furotropones 3o and 3p, respectively. Further, reaction of the tricarbonyls 3q2, 3r2 and 3s2, which were obtained by the reaction of 3-formyl-2-furylcarbinols 3a1, 3c1 and 3s1, and ethyl acetoacetate 2c, respectively, in the

presence of a catalytic amount of bismuth(III)chloride, under standard reaction conditions not only furnished the βketoesters 3q3, 3r3 and 3s3, but subsequently underwent in situ ethoxy decarbonylation, generating mono (C-8) substituted furotropones 3q, 3r and 3s, respectively, in good yields, Scheme 4. However, the reaction can be interrupted prematurely to isolate the β-ketoesters, but the case of furotropone 3i may be an exception where formation of ethoxy decarbonylation product was not observed even after prolonged reaction times. Of particular interest, reaction of the diketoaldehyde 3t2, possessing a pendent alkyne functionality, under standard base D

DOI: 10.1021/acs.joc.5b00226 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry mediated conditions failed to generate the expected furotropone 3t; however, to our surprise, it yielded a 2,3′-bifuran derivative 4 in 78% yield in a mechanism described in Scheme 5. Subtle variations across the alkynes and/or diketones can potentially generate an array of functionalized 2,3′-bifuran derivatives.9 This method thus can be a general approach for the synthesis of otherwise difficult to access, functionalized and highly substituted bifuran derivatives. Several natural products possessing cyclohepta[b]furan core are known in the literature, some of the representative examples are depicted in Figure 1. This methodology can be very much

Figure 1. Some natural products possessing cyclohepta[b]furan core.

convenient for developing short synthesis of several of these bioactive compounds. For example, frondosin B, liphagal and other natural products are synthetic challenges with their wide structural diversity and stereochemical features coupled with their interesting biological activity profiles.10 Crystal Structure of the Furotropone 3j. Molecular structure of the tropone 3j was confirmed by single crystal Xray diffraction analysis and the molecular packing arrangement in the solid state were further analyzed (see Supporting Information for details), Figure 2. Photophysical Properties. In order to better understand the photophysical properties of the newly synthesized furotropones in detail, initially UV−vis absorption spectra of the furotropone 3q under various solvent systems were recorded and the results are summarized in Figure 3a. A

Figure 3. (a) UV−vis absorption spectra of 3q (10 μM) in different solvents, and (b) fluorescence emission spectra of 3q (10 μM) in different solvents.

striking impact of solvents on the UV absorption pattern was witnessed. Among the solvents screened, a nonpolar solvent such as toluene at 10 μM concentration exhibited an absorption maximum at 332 nm (due to n−π* transition) while in a polar solvent DMSO at the same concentration, 3q displayed an absorption maximum at 338 nm, essentially indicating a bathochromic shift (red shift) of about 6 nm. On the other hand, a hypsochromic shift (blue shift) of about 18 nm was observed in case of π−π* transitions for furotropone 3q from toluene to DMSO. Further, UV−vis absorption spectra of few other di- and triketofurotropones (3b, 3c, 3e, 3g, 3h, 3j, 3k) were also recorded (see Supporting Information for details). Subsequently, the fluorescence emission spectra of furotropne 3q were also recorded in different solvents at 10 μM concentration and the results are summarized in Figure 3b and Table 2. Fluorescence emission patterns were found to be strongly solvent dependent. Solvent effect was more pronounced in n−π* transition when excited the molecule at 340 nm. Interestingly, maximum Stokes shift (97 nm) was observed in DMSO and also in ethanol (94 nm) while minimum Stokes shift was realized in acetone (41 nm). Fluorescence life expectancy (τf) was found to be maximum in THF (5.89 ns) and it was found to be least in ethanol (1.34 ns). These results perhaps indicate inherently rigid electronic nature and thus least solvent polarity dependency of

Figure 2. ORTEP diagram of 3j (CCDC 1046548) with 50% ellipsoidal probability. E

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The Journal of Organic Chemistry Table 2. Photophysical Data of 3q in Different Solvents solventa THF ACN toluene DMSO acetone EtOAc ethanol

λabs (nm)b 256, 260, 284, 266, 210, 256, 244,

330 334 332 338 334 332 337

ε

log ε

λemi (nm)

Δλstokes (nm)c

τf (ns)d

Φf

10.84 8.722 4.17 5.09 8.34 7.9 9.485

1.0350 0.940 0.620 0.7067 0.921 0.8976 0.977

402 410 406 435 375 376 431

72 76 74 97 41 44 94

5.89 3.13 2.38 3.31 1.41 1.47 1.34

0.0048 0.0145 0.0011 0.0017 0.0036 0.0083 0.0081

THF: tetrahydrofuran; ACN: acetonitrile; DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate. bπ−π* and n−π* absorption maxima. cStokes shift = λmaxemi − λmaxabs. dFluorescent lifetime. a

prefer interaction with the soft π-surfaces. Decreasing the metal ion concentration (up to 10 μM), significant influence on the fluorescence intensity was observed. From this study we have realized that furotropone 3b (and potentially other analogues) could function as a probe for the detection of Fe3+ up to 10 μM concentration.

furotropones. These results further point to their strong nonpolar character and also possible absence of push−pull electronic effects in the excited state. From Table 2, it can also be noted that the molar absorptivity (ε) for 3q in toluene solution is found to be minimum (4.17) and in THF solvent, it is maximum (10.84). Fluorescence emission spectra of few other furotropones (3b, 3c, 3e, 3g, 3h, 3j, 3k) were recorded and their fluorescence lifetimes were also measured in ethanol, which indicated that the lifetimes lie within 1.08 to 1.44 ns (see Supporting Information for details). Interesting electronic and spectroscopic properties, along with the presence of the 1,3- di- and 1,3,5-triketo groups in unique molecular environment inspired us to explore the application of furotropones as fluorescent chemosensors for cations with the potential to coordinate to these functionalities. Furotropone 3b was chosen as a model substrate and exposed to the aqueous solutions of different metal salts11 in ethanol. Almost no change in the fluorescence intensity was observed when solutions of other metal ions such as Hg2+, Pb2+, Cr2+, Cd2+, Ag+, Zn2+, Cu2+, Co2+, Fe2+, Ni2+ were tested. Furotropone 3b was found to exhibit an interesting and highly selective fluorescent molecular sensing property for Fe3+, Figure 4.12 We surmised that the 1,3-dicarbonyl moiety in 3b could

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CONCLUSIONS In summary, we have developed a modular approach to rapidly access functionalized and polysubstituted furotropones and benzofurotropones starting from readily accessible materials. The three-step protocol features directed α-alkylation of 3furancarboxaldehydes, Bi(III)-mediated furfurylation and an unusual base-mediated intramolecular aldol condensation reaction. Mono substituted (C-8) furotropones could be accessed via in situ alkoxy decarbonylation of furotropone βketoesters, disubstituted (C-7 and 8) furotropones could be synthesized in a retro-Claisen-aromatization strategy, and trisubstituted (C-5, 7 and 8) furotropones were conveniently prepared by means of a base-mediated intramolecular aldol reaction of 1,3,5-triketones. Moreover, studies directed at understanding the physicochemical properties of furotropones yielded interesting results. We have identified that these new chromophores, with their unique structural features, have potential to be highly sensitive and selective sensors for the detection of hard cations such as Fe3+, and the detection limit could be as low as 10 μM. We believe that our results could provide guidance for the design and synthesis of new troponebased polycyclic aromatic heterocycles. Further synthetic modifications of furotropones for chemosensor applications are planned.

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EXPERIMENTAL SECTION

General Experimental Methods. n-BuLi, 3-methyl benzofuran, all the aldehydes, N-methylpiperazine, N,O-dimethylhydroxylamine hydrochloride and solvents were purchased from commercial sources and were used without further purification. For thin-layer chromatography (TLC), silica aluminum foils with a fluorescent indicator (254 nm) were used and compounds were visualized by irradiation with UV light and/or by treatment with a solution of p-anisaldehyde (23 mL), concentrated H2SO4 (35 mL), and acetic acid (10 mL) in ethanol (900 mL) followed by heating. Column chromatography was performed using silica gel 100−200 mesh (approximately 15−20 g per 1 g of the crude product). Dry THF was obtained by distillation over sodium and stored over sodium wire. IR spectra were recorded on a FT-IR system as thin films or KBr pellets, as indicated, with νmax values given in reciprocal centimeters. Melting points were recorded on a digital melting point apparatus and were uncorrected. 1H NMR and 13C NMR spectra were recorded on a 400 MHz FT-NMR spectrometer. NMR shifts are reported as delta (δ) units in parts per million (ppm), and coupling constants (J) are reported in hertz (Hz). The following abbreviations are utilized to describe peak patterns when appropriate:

Figure 4. Selective sensing of Fe3+ by 3b in ethanol solvent with different concentrations of Fe3+.

serve as a suitable bidentate ligand for Fe3+ while the fused ring system could enhance the structural rigidity and change the πelectron distribution. In other words, the hard cation such as Fe3+ interacts with the hard oxygen atoms of the carbonyls present in the furoptopone 3b. The possibility of cation-π interactions are less favored since the hard cations will not F

DOI: 10.1021/acs.joc.5b00226 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

General Procedure for Step-II, Scheme 2 (Reaction of 3Formyl-2-furylcarbinols with Various 1,3-Dicarbonyls). To a solution of furfuryl alcohol (0.1 mmol, 1 equiv) in nitromethane (1 mL), were added acetylacetone (0.11 mmol, 1.1 equiv) followed by BiCl3 (0.02 mmol, 0.2 equiv) at room temperature. The reaction was stirred at room temperature until the alcohol was consumed as monitored by TLC, and the reaction mixture was quenched with aqueous saturated sodium bicarbonate solution (1−2 mL). The reaction mixture was diluted with ethyl acetate (1−2 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (1−2 mL). The organic layers were combined, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (ethyl acetate−hexanes) to afford 1,3-dicarbonyl adducts in 60− 95% yields. Spectral Data of 1,3-Dicarbonyl Adducts. Some of the 1,3dicarbonyl adducts prepared during study are already known in the literature.7,8 Complete characterization data of newly synthesized compounds is given below. 2-(2-Benzoyl-3-oxo-1-phenylbutyl)furan-3-carbaldehyde (3b2). This compound was isolated as colorless liquid starting from 40 mg of 3a1 and obtained 66 mg in 97% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax/cm−1 2925, 1722, 1673, 1600, 1546, 1443, 1325, 752; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.05− 8.02 (m, 2H), 7.62 (tt, J = 7.4 and 1.7 Hz, 1H), 7.52−7.47 (m, 4H), 7.38−7.35 (m, 2H), 7.31−7.27 (m, 1H), 7.18 (d, J = 1.9 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 5.78 (d, J = 11.5 Hz, 1H), 5.63 (d, J = 11.6 Hz, 1H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.9, 193.1, 184.7, 161.9, 142.4, 137.1, 135.9, 134.1, 129.2 (2CH), 128.9 (2CH), 128.8 (2CH), 128.4 (2CH), 128.1, 122.3, 108.7, 66.3, 43.6, 29.1; HRMS (ESI) m/z calcd for C22H18O4Na (M + Na)+ 369.1103, found 369.1104. 2-(2-Acetyl-1-(4-ethylphenyl)-3-oxobutyl)furan-3-carbaldehyde (3c2). This compound was isolated as colorless liquid starting from 50 mg of 3c1 and obtained 67 mg in 95% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax/cm−1 2965, 1733, 1702, 1681, 1574, 1514, 1471, 1358, 1124, 746. 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.27 (m, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 2.0 Hz, 1H), 5.38 (d, J = 11.8 Hz, 1H), 4.92 (d, J = 12.0 Hz, 1H), 2.60 (q, J = 7.0 Hz, 2H), 2.17 (s, 3H), 2.03 (s, 3H), 1.20 (t, J = 7.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.1, 200.9, 184.7, 161.9, 144.0, 142.5, 134.2, 128.7 (2CH), 128.0 (2CH), 122.0, 109.7, 71.7, 42.8, 30.2, 29.4, 28.3, 15.2; HRMS (ESI) m/z calcd for C19H20O4Li (M + Li)+ 319.1522, found 319.1565. 2-(2-Benzoyl-1-(4-ethylphenyl)-3-oxobutyl)furan-3-carbaldehyde (3d2). This compound was isolated as colorless liquid starting from 50 mg of 3c1 and obtained 76 mg in 94% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax /cm−1 2922, 1725, 1680, 1448, 1358, 1267, 1125, 1023, 748; 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.03 (dd, J = 8.5 and 1.3 Hz, 2H), 7.62 (tt, J = 7.4 and 1.3 Hz, 1H), 7.51−7.48 (m, 2H), 7.39 (tt, J = 10.1 and 1.7 Hz, 2H), 7.20−7.147 (m, 3H), 6.58 (d, J = 2.0 Hz, 1H), 5.76 (d, J = 11.5 Hz, 1H), 5.60 (d, J = 11.5 Hz, 1H), 2.63 (q, J = 7.6 Hz, 2H), 2.04 (s, 3H), 1.22 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.1, 193.2, 184.7, 162.3, 144.1, 142.3, 135.9, 134.1, 134.0, 128.9 (2CH), 128.8 (2CH), 128.7 (2CH), 128.3 (2CH), 122.2, 66.4, 43.2, 29.0, 28.4, 18.6, 15.3; HRMS (ESI) m/z calcd for C24H22O4Na (M + Na)+ 397.1416, found 397.1432. 2-(2-Benzoyl-1-(furan-2-yl)-3-oxobutyl)furan-3-carbaldehyde (3e2). This compound isolated as colorless liquid starting from 40 mg of 3e1 and obtained 49 mg in 71% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax/cm−1 2922, 1725, 1680, 1594, 1417, 1269, 1012, 744; 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.05− 8.02 (m, 2H), 7.54−7.47 (m, 4H), 7.40 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 1.8 and 0.7 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.14 (dd, J = 3.0 and 1.8 Hz, 1H), 6.11 (d, J = 3.2 Hz, 1H), 5.81 (d, J = 10.3 Hz, 1H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.7, 192.9, 184.8, 159.6, 149.7, 142.8, 142.4, 136.1, 134.1, 128.9 (2CH), 128.8 (2CH), 122.9, 110.6, 108.9, 108.0, 63.2, 37.3, 29.0; HRMS (ESI) m/z calcd for C20H16O5Na (M + Na)+ 359.0895, found 359.0898.

br = broad, s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. Proton chemical shifts are given in δ relative to tetramethylsilane (δ 0.00 ppm) in CDCl3. Carbon chemical shifts are internally referenced to the deuterated solvent signals in CDCl3 (δ 77.1 ppm). High-resolution mass spectra were recorded on a Q-TOF mass spectrometer. General Procedure for Step-I, Scheme 2 (Synthesis of 3Formyl-2-furylcarbinols Starting from 3-Furancarboxaldehyes). To a solution of N-methylpiperazine (NMP, 0.07 mL, 0.66 mmol) in THF (2 mL) at −78 °C was added n-BuLi (2 M in cyclohexane, 0.33 mL, 0.66 mmol). After 15 min, 3-furaldehyde (50 mg, 0.045 mL, 0.52 mmol) was added, and then the reaction mixture was stirred for an additional 30 min. A cyclohexane solution of n-BuLi (0.66 mL, 1.32 mmol) was added, and the mixture was stirred for an additional 15 min, and then the mixture was warmed to −30 °C in 2 h. The solution was again cooled to −78 °C and an aldehyde (1.02 mmol) was added dropwise over 5 min. The mixture was warmed to room temperature over 30 min. The reaction progress was monitored by TLC. Reaction mixture was quenched with saturated aq. ammonium chloride solution and extracted with ethyl acetate. The organic extracts were combined, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate−hexanes) to afford 3-formyl-2furylcarbinols in 60−80% yields. Spectral Data of Newly Synthesized Alcohols. Some of the 3formyl-2-furylcarbinols prepared during this study are already known in the literature.7,8 Complete characterization data of newly synthesized compounds is given below. 2-(Hydroxy(thiophen-2-yl)methyl)furan-3-carbaldehyde (3g1). This compound was isolated as colorless liquid: Rf = 0.4 (EtOAc/ Hexane = 3/7); IR (thin film, neat) νmax/cm−1 3372, 2872, 1672, 1580, 1516, 1422, 1237, 1127, 1024, 805; 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.32 (m, 1H), 6.98 (m, 2H), 6.83 (d, J = 1.9 Hz, 1H), 6.30 (d, J = 7.0 Hz, 1H), 4.69 (d, J = 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.0, 162.1, 143.7, 142.5, 126.9, 126.1, 125.2, 122.5, 110.2, 66.6; HRMS (ESI) m/z calcd for C10H9O3S (M + H)+ 209.0272, found 209.0277. 2-([1,1′-Biphenyl]-4-yl(hydroxy)methyl)furan-3-carbaldehyde (3i1). This compound was isolated as colorless liquid: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax/cm−1 3370, 2870, 1670, 1578, 1514, 1418, 1235, 1022, 703; 1H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 7.63−7.58 (m, 4H), 7.51−7.44 (m, 4H), 7.42 (d, J = 2.0 Hz, 1H), 7.37 (tt, J = 8.5 and 1.2 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.15 (d, J = 7.3 Hz, 1H), 4.49 (d, J = 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.2, 163.2, 142.4, 141.3, 140.5, 139.1, 128.8 (2CH), 127.5 (2CH), 127.3, 127.1 (2CH), 126.6 (2CH), 122.6, 110.2, 70.3; HRMS (ESI) m/z calcd for C18H15O3 (M + H)+ 279.1021, found 279.1026. 2-(Hydroxy(phenyl)methyl)benzofuran-3-carbaldehyde (3m1). This compound was isolated as colorless liquid: Rf = 0.4 (EtOAc/ Hexane = 3/7); IR (thin film, neat) νmax/cm−1 3313, 3031, 1661, 1575, 1495, 1479, 1452, 1176, 1011, 748; 1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 8.12 (dd, J = 6.8 and 3.3 Hz, 1H), 7.53−7.51 (m, 3H), 7.43−7.36 (m, 5H), 6.29 (d, J = 5.5 Hz, 1H), 4.03 (d, J = 5.6 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 186.6, 166.7, 139.6, 128.9 (2CH), 128.7, 126.4 (2CH), 125.8, 125.0, 124.8, 121.4, 117.5, 111.5, 101.9, 65.4; HRMS (ESI) m/z calcd for C16H13O3 (M + H)+ 253.0865, found 253.0839. 2-((3-Fluorophenyl)(hydroxy)methyl)furan-3-carbaldehyde (3s1). This compound was isolated as colorless liquid: Rf = 0.4 (EtOAc/ Hexane = 3/7); IR (thin film, neat) νmax/cm−1 3363, 2927, 1673, 1615, 1592, 1488, 1451, 1250, 1129, 1024, 787; 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.37−7.34 (m, 1H), 7.18 (dd, J = 13.2 and 8.9, 2H), 7.02 (td, J = 8.4 and 2.5 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.08 (d, J = 5.3 Hz, 1H), 4.73 (d, J = 6.8 Hz,1H); 13 C NMR (100 MHz, CDCl3) δ 187.3, 162.9 (d, J = 245.06 Hz), 162.6, 142.6, 142.5, 130.1 (d, J = 8.05 Hz), 122.6, 121.7, 115.2 (d, J = 20.9 Hz), 113.2 (d, J = 22.51 Hz), 110.4, 69.8; 19F NMR (376.4 MHz, CDCl3) δ −112.15; HRMS (ESI) m/z calcd for C12H8FO2 (M − OH)+ 203.0509, found 203.0498. G

DOI: 10.1021/acs.joc.5b00226 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

1597, 1448, 1274, 1250, 1181, 1013, 742; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.07−8.05 (m, 2H), 7.82−7.80 (m, 2H), 7.55−7.53 (m, 2H), 7.51−7.50 (m, 2H), 7.45 (s, 1H), 7.49−7.47 (m, 2H), 7.43−7.43 (m, 1H), 7.37 (dd, J = 1.7 and 0.6 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 6.36 (d, J = 3.1 Hz, 1H), 6.30−6.28 (m, 1H), 5.79 (d, J = 11.4 Hz, 1H), 5.60 (d, J = 11.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 193.0, 190.5, 184.8, 182.1, 159.9, 156.2, 149.7, 143.0, 142.7, 142.6, 134.1, 132.9, 129.0, 128.95, 128.91 (2CH), 128.7 (2CH), 127.1 (2CH), 122.7, 110.8, 108.4, 107.8, 96.2, 60.2, 37.9; HRMS (ESI) m/z calcd for C27H20O6Na (M + Na)+ 463.1168, found 463.1158. 2-(1-([1,1′-Biphenyl]-4-yl)-2-benzoyl-3,5-dioxo-5-phenylpentyl)furan-3-carbaldehyde (3l2). This compound was isolated as colorless liquid starting from 40 mg of 3i1 and obtained 52 mg in 70% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax /cm−1 2925, 2853, 1734, 1681, 1597, 1487, 1448, 1123, 1077, 821, 738; 1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 8.07−8.05 (m, 2H), 7.82−7.80 (m, 2H), 7.51−7.47 (m, 7H), 7.45−7.43 (m, 6H), 7.37−7.36 (m, 1H), 7.24 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 6.35 (d, J = 3.6 Hz, 1H), 6.31 (s, 1H), 6.30−6.29 (m, 1H), 6.20 (d, J = 3.6 Hz, 1H), 5.60 (d, J = 11.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 193.0, 190.5, 184.9, 182.1, 159.8, 149.7, 142.7, 142.3, 135.7, 135.7, 134.0, 134.6, 134.0, 133.5, 132.9, 129.0 (2CH), 128.9 (2CH), 128.8 (3CH), 128.7 (3CH), 128.1, 127.1 (2CH), 122.7, 110.8, 108.6, 108.4, 96.2, 60.2, 37.9; HRMS (ESI) m/z calcd for C35H26O5Na (M + Na)+ 549.1678, found 549.1661. 2-(2-Acetyl-3-oxo-1-phenylbutyl)benzofuran-3-carbaldehyde (3m2). This compound was isolated as colorless liquid starting from 30 mg of 3m1 and obtained 23 mg in 60% yield: Rf = 0.4 (EtOAc/ Hexane = 3/7); IR (thin film, neat) νmax/cm−1 2947, 2868, 1720, 1697, 1681, 1487, 1451, 1124, 760; 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.11−8.09 (m, 1H), 7.52−7.49 (m, 1H), 7.46−7.44 (m, 2H), 7.40 (d, J = 4.8 Hz, 1H), 7.37−7.33 (m, 3H), 5.55 (d, J = 11.8 Hz, 1H), 5.10 (q, J = 11.8 Hz, 2H), 2.23 (s, 3H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.9, 200.3, 184.7, 166.0, 153.8, 136.6, 129.4 (2CH), 128.6, 128.2 (2CH), 125.6, 124.9, 124.6, 121.9, 117.1, 111.0, 71.2, 43.2, 30.3, 29.7; HRMS (ESI) m/z calcd for C21H18O4Na (M + Na)+ 357.1103, found 357.1103. 2-(2-Benzoyl-3-oxo-1-phenylbutyl)benzofuran-3-carbaldehyde (3n2). This compound was isolated as colorless liquid starting from 45 mg of 3m1 and obtained 45 mg in 65% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax/cm−1 2962, 2929, 1738, 1704, 1681, 1575, 1487, 1125, 765, 747; 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 8.06−8.04 (m, 2H), 7.97−7.95 (m, 2H), 7.49−7.45 (m, 2H), 7.42−7.40 (m, 3H), 7.38−7.35 (m, 3H), 7.22−7.18 (m, 2H), 5.97 (d, J = 11.5 Hz, 1H), 5.80 (d, J = 11.3 Hz, 1H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 193.1, 184.8, 166.7, 153.9, 137.0, 134.1, 129.0 (2CH), 128.9 (2CH), 128.8 (2CH), 128.5, 128.3 (2CH), 127.0, 125.5, 124.9, 124.6, 122.07, 117.2, 110.0, 65.3, 43.7, 29.3; HRMS (ESI) m/z calcd for C26H20O4Na (M + Na)+ 419.1259, found 419.1250. 2-(2-Acetyl-2-methyl-3-oxo-1-phenylbutyl)furan-3-carbaldehyde (3o2). This compound was isolated as colorless liquid starting from 30 mg of 3a1 and obtained 35 mg in 80% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax/cm−1 2925, 1738, 1716, 1682, 1580, 1494, 1454, 1369, 1246, 1145, 1045, 758; 1H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.29−7.27 (m, 5H), 6.7 (d, J = 1.9 Hz, 1H), 5.98 (s, 1H), 2.05 (s, 3H), 2.06 (s, 3H), 1.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 205.2, 204.0, 185.0, 162.2, 142.2, 136.8, 129.8 (2CH), 128.6 (2CH), 127.8, 122.9, 108.8, 71.4, 45.5, 27.2, 26.5, 16.5; HRMS (ESI) m/z calcd for C18H19O4 (M + H)+ 299.1283, found 299.1249. 2-(2-Acetyl-1-(4-ethylphenyl)-2-methyl-3-oxobutyl)furan-3-carbaldehyde (3p2). This compound was isolated as colorless liquid starting from 47 mg of 3c1 and obtained 59 mg in 90% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax/cm−1 3363, 1673, 1583, 1503, 1418, 1274, 1145, 1128, 1012; 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 6.72 (d, J = 1.9 Hz, 1H), 5.90 (s, 1H), 2.60 (q, J = 7.6 Hz, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 1.73 (s, 3H), 1.20

2-(2-Benzoyl-1-(5-methylfuran-2-yl)-3-oxobutyl)furan-3-carbaldehyde (3f2). This compound was isolated as colorless liquid starting from 40 mg of 3f1 and obtained 50 mg in 74% yield: Rf = 0.4 (EtOAc/ Hexane = 3/7); IR (thin film, neat) νmax/cm−1 2922, 1725, 1680, 1448, 1358, 1267, 1125, 1023, 748, 695; 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.06−8.04 (m, 2H), 7.54−7.47 (m, 4H), 7.39 (d, J = 1.9 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 5.97 (d, J = 11.3 Hz, 1H), 5.94 (d, J = 3.0 Hz, 1H), 5.79 (d, J = 11.3 Hz, 1H), 2.12 (s, 3H), 2.04 (d, J = 0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.9, 192.7, 184.8, 159.8, 152.5, 147.7, 142.6, 136.6, 134.1, 128.9 (2CH), 128.8 (2CH), 122.8, 109.1, 108.8, 106.7, 64.3, 37.3, 28.4, 13.5; HRMS (ESI) m/z calcd for C21H18O5Na (M + Na)+ 373.1052, found 373.1073. 2-(2-Acetyl-3-oxo-1-(thiophen-2-yl)butyl)furan-3-carbaldehyde (3g2). This compound was isolated as colorless liquid starting from 40 mg of 3g1 and obtained 42 mg in 75% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax/cm−1 2997, 2866, 1721, 1698, 1680, 1610, 1512, 1394, 1360, 1250, 1182, 1088, 1045, 744; 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 5.2 and 1.0 Hz, 1H), 7.01 (dd, J = 3.5 and 0.6 Hz, 1H), 6.94−6.92 (m, 1H), 6.70 (d, J = 2.0 Hz, 1H), 5.75 (d, J = 5.8 Hz, 1H), 4.91 (d, J = 5.8 Hz, 1H), 2.16 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.7, 200.2, 184.7, 160.2, 142.6, 139.3, 127.1, 126.5, 125.7, 122.1, 109.1, 72.3, 38.1, 30.1, 29.4; HRMS (ESI) m/z calcd for C15H14O4SNa (M + Na)+ 313.0510, found 313.0520. 2-(2-Benzoyl-3-oxo-1-(thiophen-2-yl)butyl)furan-3-carbaldehyde (3h2). This compound was isolated as colorless liquid starting from 40 mg of 3g1 and obtained 63 mg in 94% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax/cm−1 2956, 2870, 1721, 1698, 1682, 1573, 1519, 1418, 1366, 1124, 759; 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.01 (dd, J = 0.9 Hz, 3H), 7.51−7.47 (m, 2H), 7.43 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 1.0 Hz, 1H), 6.95−6.93 (m, 1H), 6.79− 6.77 (m, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.02 (d, J = 11.3 Hz, 1H), 5.79 (d, J = 11.3 Hz, 1H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.9, 192.7, 184.7, 160.8, 142.7, 139.6, 136.4, 134.1, 128.9 (2CH), 128.8 (2CH), 126.9, 126.6, 125.3, 122.3, 109.1, 66.6, 38.6, 28.8; HRMS (ESI) m/z calcd for C20H16O4SNa (M + Na)+ 375.0667, found 375.0663. Ethyl 2-([1,1′-biphenyl]-4-yl(3-formylfuran-2-yl)methyl)-3-oxobutanoate (3i2). This compound was isolated as colorless liquid starting from 55 mg of 3i1 and obtained 61 mg in 80% yield: Rf = 0.4 (EtOAc/ Hexane = 3/7); IR (thin film, neat) νmax/cm−1 2957, 2870, 1722, 1697, 1680, 1570, 1514, 1413, 1370, 1124, 766; 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 7.62−7.61 (m, 1H), 7.54−7.53 (m, 3H), 7.44−7.42 (m, 4H), 7.39 (d, J = 2.0 Hz, 1H), 7.36−7.35 (m, 1H), 6.71 (d, J = 2.0 Hz, 1H), 5.38 (d, J = 5.3 Hz, 1H), 4.76 (d, J = 3.3 Hz, 1H), 4.04 (qd, J = 7.1 and 1.8 Hz, 2H), 2.29 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 184.5, 166.7, 161.9, 142.6, 140.7, 140.2, 139.8, 136.4, 128.8 (2CH), 128.7 (2CH), 127.7 (2CH), 127.5 (2CH), 127.3, 109.6, 64.1, 63.1, 61.9, 42.3, 29.0; HRMS (ESI) m/z calcd for C24H22O5Na (M + Na)+ 413.1365, found 413.1373. 2-(2-Benzoyl-3,5-dioxo-1,5-diphenylpentyl)furan-3-carbaldehyde (3j2). This compound was isolated as colorless liquid starting from 40 mg of 3a1 and obtained 70 mg in 73% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax /cm−1 2924, 2852, 1681, 1597, 1493, 1448, 1278, 1026, 744, 695; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.03−8.00 (m, 2H), 7.80−7.78 (m, 1H), 7.63−7.62 (m, 1H), 7.61−7.60 (m, 2H), 7.54−7.53 (m, 1H), 7.52−7.51 (m, 1H), 7.50− 7.49 (m, 2H), 7.48−7.47 (m, 2H), 7.34−7.32 (m, 1H), 7.21 (s, 2H), 7.17−7.16 (m, 1H), 7.13−7.11 (m, 1H), 6.38−6.36 (m, 1H), 5.65 (d, J = 11.5 Hz, 1H), 5.55 (d, J = 11.5 Hz, 1H), 5.03 (dd, J = 10.7 and 4.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 193.6, 193.6, 193.0, 182.0, 159.0, 142.4, 137.9, 137.3, 135.9, 133.9, 133.5, 132.4, 129.3 (2CH), 128.9 (2CH), 128.8 (2CH), 128.7 (2CH), 128.1 (2CH), 127.1 (2CH), 122.2, 112.6, 62.3, 53.4, 44.4; HRMS (ESI) m/z calcd for C29H22O5Na (M + Na)+ 473.1365, found 473.1384. 2-(2-Benzoyl-1-(furan-2-yl)-3,5-dioxo-5-phenylpentyl)furan-3carbaldehyde (3k2). This compound isolated as colorless liquid starting from 45 mg of 3e1 and obtained 77 mg in 75% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax /cm−1 2926, 1682, H

DOI: 10.1021/acs.joc.5b00226 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.2, 204.2, 185.1, 162.5, 143.8, 142.5, 133.9, 129.7 (2CH), 128.1 (2CH), 122.9, 108.7, 71.5, 45.2, 28.3, 27.2, 26.6, 16.5, 15.2; HRMS (ESI) m/z calcd for C20H22O4Na (M + Na)+ 349.1416, found 349.1417. Ethyl 2-((4-ethylphenyl)(3-formylfuran-2-yl)methyl)-3-oxobutanoate (3r2) major. This compound was isolated as colorless liquid starting from 20 mg of 3c1 and obtained 19 mg in 65% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax /cm−1 2966, 1743, 1720, 1681, 1514, 1245, 1124, 750; 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.30−7.28 (m, 2H), 7.16−7.14 (m, 2H), 6.69 (d, J = 2.0 Hz, 1H), 5.32 (d, J = 4.0 Hz, 1H), 4.70 (d, J = 3.7 Hz, 1H), 4.10−4.07 (m, 2H), 2.60 (q, J = 7.5 Hz, 2H), 2.26 (s, 3H), 1.20 (td, J = 7.6 and 2.6 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.5, 184.7, 166.6, 162.5, 143.9, 142.5, 134.6, 128.6 (2CH), 128.3 (2CH), 122.1, 108.8, 82.6, 61.9, 42.2, 29.4, 28.4, 15.4, 13.7; HRMS (ESI) m/z calcd for C20H22O5Na (M + Na)+ 365.1365, found 365.1356. Ethyl 2-((3-fluorophenyl)(3-formylfuran-2-yl)methyl)-3-oxobutanoate (3s2). This compound was isolated as colorless liquid starting from 30 mg of 3s1 and obtained 31 mg in 69% yield: Rf = 0.4 (EtOAc/ Hexane = 3/7); IR (thin film, neat) νmax /cm−1 2958, 2927, 1733, 1681, 1521, 1418, 1359, 1131, 1046, 888; 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.19−7.16 (m, 2H), 6.99−6.94 (m, 2H), 6.70 (d, J = 2.0 Hz, 1H), 5.37 (d, J = 6.3 Hz, 1H), 5.34 (d, J = 6.3 Hz, 1H), 4.00−4.10 (m, 2H), 2.28 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.9, 184.6, 166.4, 162.8 (d, J = 245.86 Hz), 161.4, 142.7, 139.8 (d, J = 7.00 Hz), 130.6 (d, J = 8.15 Hz), 124.1, 122.5, 115.3 (d, J = 22.23 Hz), 115.0 (d, J = 20.7 Hz), 109.2, 62.9, 62.1, 42.2, 30.9, 13.9; 19F NMR (376.4 MHz, CDCl3) δ −111.8; HRMS (ESI) m/z calcd for C18H17O5FNa (M + Na)+ 355.0958, found 355.0967. 2-(1-Phenyloct-2-yn-1-yl)furan-3-carbaldehyde (3t2). This compound was isolated as a colorless liquid starting from 30 mg of 3t1 and obtained 42 mg in 85% yield: Rf = 0.4 (EtOAc/Hexane = 3/7); IR (thin film, neat) νmax/cm−1 3363, 2123, 1705, 1673, 1583, 1503, 1418, 1274, 1145, 1128, 1012, 896, 785; 1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.94 (dd, J = 8.5 and 1.3 Hz, 2H), 7.60 (m, 3H), 7.23 (dd, J = 2.0 and 0.5 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 5.40 (d, J = 10.4 Hz, 1H), 5.23 (td, J = 10.4 and 2.3 Hz, 1H), 2.35 (s, 3H) 2.19 (td, J = 7.2 and 1.8 Hz, 2H), 1.35−1.29 (m, 4H), 1.11−1.06 (s, 2H), 0.77 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 192.3, 184.4, 158.6, 142.7, 135.6, 134.2, 129.1 (2CH), 128.9 (2CH), 122.8, 108.3, 86.6, 74.4, 66.3, 30.9, 29.9, 28.3, 28.0, 22.1, 18.6, 13.9; HRMS (ESI) m/z calcd for C23H25O4 (M + H)+ 365.1753, found 365.1755. General Procedure for Step-III, Scheme 2 (Base Mediated Intramolecular Aldol Condensation of the 1,3-Dicarbonyl Adducts for the Synthesis of Furotropones). To a solution of the 1,3-dicarbonyl adduct (0.06 mmol, 1 equiv) in 1 mL DMF, sodium carbonate (5 mg, 1 equiv) was added under nitrogen atmosphere. The flask was placed in an oil bath (80 °C) and stirring was continued for 3 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic extracts were combined, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate−hexanes) to afford furotropone. Spectral Data of Furotropones. Some of the furotropones prepared during study are already known in the literature.7,8 Complete characterization data of newly synthesized compounds is given below. 7-Benzoyl-8-phenyl-6H-cyclohepta[b]furan-6-one (3b). This compound was isolated as a pale yellow solid (22 mg, 75%): mp = 266−269 °C; Rf = 0.4 (EtOAc/Hexane= 2/3); IR (thin film, neat) νmax/cm−1 2923, 1711, 1673, 1535, 1497, 1454, 1343, 1260, 1096, 734; 1 H NMR (400 MHz, CDCl3) δ 7.73−7.70 (m, 2H), 7.62 (d, J = 11.8 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.46 (tt, J = 7.3 and 1.2 Hz, 1H), 7.34−7.30 (m, 3H), 7.30−7.20 (m, 4H), 7.14 (d, J = 11.8 Hz, 1H), 6.90 (d, J = 1.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 195.3, 185.6, 153.6, 145.8, 144.1, 138.4, 137.4, 136.7, 133.7, 133.0, 131.5, 129.4, 129.3, 129.3, 128.7 (2CH), 128.7, 128.6, 128.3 (2CH), 127.8, 113.0; HRMS (ESI) m/z calcd for C22H15O3 (M + H)+ 327.1000, found 327.0990.

7-Acetyl-8-(4-ethylphenyl)-6H-cyclohepta[b]furan-6-one (3c). This compound was isolated as a pale yellow solid (28 mg, 74%): mp = 250−253 °C; Rf = 0.4 (EtOAc/Hexane = 2/3); IR (thin film, neat) νmax/cm−1 2963, 2925, 2854, 1711, 1621, 1578, 1538, 1496, 1454, 1340, 1136, 1091, 816; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 11.8 Hz, 1H), 7.28 (m, 4H), 7.10 (d, J = 11.8 Hz, 1H), 6.85 (d, J = 1.8 Hz, 1H), 2.73 (q, J = 7.6 Hz, 2H), 2.10 (s, 3H), 1.30 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.2, 185.1, 153.7, 146.3, 145.7, 145.2, 137.5, 136.8, 131.6, 131.0, 129.2 (2CH), 128.3, 127.8 (2CH), 113.0, 31.0, 28.6, 15.1; HRMS (ESI) m/z calcd for C19H17O3 (M + H)+ 293.1178, found 293.1176. 7-Benzoyl-8-(4-ethylphenyl)-6H-cyclohepta[b]furan-6-one (3d). This compound was isolated as a pale yellow solid (23 mg, 62%): mp = 260−262 °C; Rf = 0.4 (EtOAc/Hexane = 2/3); IR (thin film, neat) νmax /cm−1 2960, 2926, 1671, 1636, 1536, 1494, 813; 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 6.4 and 1.3 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 11.8, 1H), 7.46 (tt, J = 8.6, 2.4, and 1.2 Hz, 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.14 (d, J = 11.8 Hz, 2H), 7.08 (brs, 3H), 6.90 (d, J = 2.0 Hz, 1H), 2.60 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 195.5, 185.6, 153.7, 145.7, 145.7, 144.7, 144.2, 138.7, 137.4, 136.8, 132.9, 131.5, 130.9, 128.7 (2CH), 128.6, 128.3 (2CH), 127.4, 127.3, 127.3, 113.0, 28.5, 15.0; HRMS (ESI) m/z calcd for C24H19O3 (M + H)+ 355.1334, found 355.1337. 7-Benzoyl-8-(furan-2-yl)-6H-cyclohepta[b]furan-6-one (3e). This compound was isolated as a pale yellow solid (34 mg, 91%): mp = 252−255 °C; Rf = 0.4 (EtOAc/Hexane = 2/3); IR (thin film, neat) νmax/cm−1 3145, 2924, 2853, 1675, 1574, 1544, 1498, 1449, 1336, 1255, 831, 693; 1H NMR (400 MHz, CDCl3) δ 7.90−7.87 (m, 2H), 7.75 (d, J = 1.9 Hz, 1H), 7.55−7.49 (m, 2H), 7.42−7.38 (m, 2H), 7.32 (dd, J = 1.7 and 0.7, 1H), 7.05 (d, J = 11.7 Hz, 1H), 6.93 (dd, J = 3.4 and 0.6 Hz, 1H), 6.90 (d, J = 1.9 Hz, 1H). 6.42 (q, J = 1.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 195.3, 185.5, 151.8, 145.4, 145.2, 144.2, 142.5, 137.2, 136.7, 132.9, 131.1, 128.7, 128.6 (2CH), 128.4 (2CH), 127.4, 116.8, 113.1, 111.8; HRMS (ESI) m/z calcd for C20H13O4 (M + H)+ 317.0814, found 317.0823. 7-Benzoyl-8-(5-methylfuran-2-yl)-6H-cyclohepta[b]furan-6-one (3f). This compound was isolated as a pale yellow solid (30 mg, 74%): mp = 255−258 °C; Rf = 0.4 (EtOAc/Hexane = 2/3); IR (thin film, neat) νmax/cm−1 2923, 2852, 1678, 1623, 1535, 1497, 1448, 1361, 1249, 1096, 833; 1H NMR (400 MHz, CDCl3) δ 7.95−7.92 (m, 2H), 7.74 (d, J = 1.9 Hz, 1H), 7.53−7.49 (m, 2H), 7.44−7.40 (m, 2H), 7.04−7.00 (m, 2H), 6.88 (d, J = 1.9 Hz, 1H), 6.06−6.04 (m, 1H), 1.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.6, 185.8, 155.0, 151.5, 144.9, 143.7, 141.1, 137.3, 137.2, 132.6, 130.8, 128.5 (3CH), 128.3 (2CH), 127.2, 119.0, 113.1, 108.6, 13.1; HRMS (ESI) m/z calcd for C21H15O4 (M + H)+ 331.0970, found 331.0953. 7-Acetyl-8-(thiophen-2-yl)-6H-cyclohepta[b]furan-6-one (3g). This compound was isolated as a pale yellow solid (13 mg, 70%): mp = 250−253 °C; Rf = 0.4 (EtOAc/Hexane = 2/3); IR (thin film, neat) νmax/cm−1 3132, 2922, 1708, 1616, 1573, 1537, 1496, 1452, 1325, 1165, 1089, 830, 794; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 1.9 Hz, 1H), 7.57 (dd, J = 4.9 and 1.4 Hz, 1H), 7.57 (d, J = 11.8 Hz, 1H), 7.14 (m, 2H), 7.08 (d, J = 11.8 Hz, 1H), 6.87 (d, J = 1.9 Hz, 1H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.7, 184.6, 147.2, 145.6, 137.4, 137.1, 132.9, 131.6, 131.3, 130.1, 128.5, 128.1, 127.0, 113.1, 30.6; HRMS (ESI) m/z calcd for C15H11O3S (M + H)+ 271.0429, found 271.0440. 7-Benzoyl-8-(thiophen-2-yl)-6H-cyclohepta[b]furan-6-one (3h). This compound was isolated as a pale yellow solid (18 mg, 95%): mp = 260−263 °C; Rf = 0.4 (EtOAc/Hexane = 2/3); IR (thin film, neat) νmax/cm−1 3112, 2954, 2853, 1673, 1537, 1494, 1452, 1356, 1328, 1258, 1092, 823; 1H NMR (400 MHz, CDCl3) δ 7.77−7.76 (m, 2H), 7.68 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 11.8 Hz, 1H), 7.48 (tt, J = 7.4 and 1.7 Hz, 1H), 7.35 (m, 3H), 7.11 (d, J = 11.8 Hz, 1H), 7.01 (dd, J = 3.6 and 1.2 Hz, 1H), 6.91 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 195.0, 185.1, 153.2, 145.7, 145.2, 137.3, 136.3, 133.2, 133.1, 132.1, 131.5, 131.2, 128.8 (2CH), 128.5, 128.4 (2CH), 128.41, 126.5, 113.2. HRMS (ESI) m/z calcd for C20H13O3S (M + H)+ 333.0585, found 333.0598. I

DOI: 10.1021/acs.joc.5b00226 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

1281, 883, 819; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 11.8 Hz, 1H), 7.99−7.97 (m, 1H), 7.74−7.71 (m, 2H), 7.54−7.51 (m, 1H), 7.50−7.45 (m, 4H), 7.35 (t, J = 1.5 Hz, 1H), 7.33−7.28 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 195.1, 185.4, 155.1, 154.5, 147.6, 147.3, 146.3, 139.0, 137.5, 136.5, 133.7, 133.1, 129.1, 128.7 (2CH), 128.6, 128.5, 128.4 (2CH), 127.9, 127.9, 125.9, 124.5, 123.7, 120.1, 112.3; HRMS (ESI) m/z calcd for C26H17O3 (M + H)+ 377.1178, found 377.1179. 7-Methyl-8-phenyl-6H-cyclohepta[b]furan-6-one (3o). This compound was isolated as a pale yellow solid (14 mg, 60%): mp = 261− 263 °C; Rf = 0.4 (EtOAc/Hexane = 1/1); IR (thin film, neat) νmax/ cm−1 2928, 1710, 1620, 1575, 1536, 1452, 1356, 1352, 1326, 830, 716; 1 H NMR (400 MHz, CDCl3) δ 7.55−7.47 (m, 5H), 7.26−7.24 (m, 2H), 7.10 (d, J = 11.9 Hz, 1H), 6.79 (d, J = 1.9 Hz, 1H), 2.03 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 187.3, 154.2, 144.3, 142.3, 139.1, 138.3, 134.5, 129.8, 128.5 (2CH), 128.2 (2CH), 127.9, 126.6, 112.0, 19.5; HRMS (ESI) m/z calcd for C16H13O2 (M + H)+ 237.0900, found 237.0909. 7-Benzoyl-8-(4-ethylphenyl)-6H-cyclohepta[b]furan-6-one (3p). This compound was isolated as a pale yellow solid (14 mg, 62%): mp = 268−271 °C; Rf = 0.4 (EtOAc/Hexane = 2/3); IR (thin film, neat) νmax/cm−1 2900, 1715, 1690, 1620, 1470, 1430, 1356, 1351, 1315, 1270, 830; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 1.9 Hz, 1H), 7.47 (d, J = 11.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 11.8 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 2.78 (q, J = 7.6 Hz, 2H), 2.04 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H) .13C NMR (100 MHz, CDCl3) δ 187.3, 144.3, 143.8, 142.9, 139.3, 135.5, 134.5, 130.2, 129.8, 128.1 (2CH), 128.0 (2CH), 126.5, 112.0, 28.6, 19.6, 15.3; HRMS (ESI) m/z calcd for C18H17O2 (M + H)+ 265.1229, found 265.1227. 8-(4-Ethylphenyl)-6H-cyclohepta[b]furan-6-one (3r). This compound was isolated as a pale yellow liquid (12 mg, 60%): Rf = 0.4 (EtOAc/Hexane = 1/1); IR (thin film, neat) νmax/cm−1 2963, 2926, 2854, 1710, 1620, 1590, 1540, 1496, 1460, 1350, 1090, 847; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 2.0 Hz, 1H), 7.52−7.48 (m, 3H), 7.36−7.33 (m, 2H), 7.06−7.02 (m, 2H), 6.85 (d, J = 1.8 Hz, 1H), 2.76 (q, J = 7.7 Hz, 2H), 1.33 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 186.9, 153.4, 145.5, 144.6, 140.7, 136.3, 136.0, 134.8, 131.4, 129.1 (2CH), 128.4, 127.9 (2CH), 113.0, 28.6, 15.3; HRMS (ESI) m/ z calcd for C17H15O2 (M + H)+ 251.1072, found 251.1071. 8-(3-Fluorophenyl)-6H-cyclohepta[b]furan-6-one (3s). This compound was isolated as a pale yellow liquid (12 mg, 55%): Rf = 0.4 (EtOAc/Hexane = 1/1); IR (thin film, neat) νmax/cm−1 2924, 2853, 1730, 1621, 1545, 1498, 1455, 1343, 1259, 1092, 1041, 867, 789; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 11.5 Hz, 1H), 7.49−7.45 (m, 1H), 7.34−7.29 (m, 2H), 7.21 (dt, J = 8.4 and 1.9, 1H), 7.04 (dd, J = 11.7 and 2.3 Hz, 2H), 6.87 (d, J = 2.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 186.7, 156.2 (d, J = 226.96 Hz), 144.8, 139.4, 136.5, 136.1, 131.5, 130.9, 130.0 (d, J = 8.16 Hz), 128.6, 126.3, 124.8, 116.4 (d, J = 22.77 Hz), 116.1 (d, J = 20.71 Hz), 113.1; 19 F NMR (376.4 MHz, CDCl3) δ −112.6; HRMS (ESI) m/z calcd for C15H10FO2 (M + H)+ 241.0665, found 241.0667. 4′-Acetyl-2′-hexyl-5′-methyl-[2,3′-bifuran]-3-carbaldehyde (4). This compound was isolated as a colorless liquid (27 mg, 78%): Rf = 0.3 (EtOAc/Hexane = 1/5); IR (thin film, neat) νmax/cm−1 3059, 2925, 1673, 1597, 1579, 1538, 1494, 1337, 1286, 1006, 739; 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.66−7.64 (m, 2H), 7.46 (tt, J = 7.4 and 1.2 Hz, 1H), 7.34−7.30 (m, 2H), 7.23 (dd, J = 2.0 and 0.5 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 2.67 (t, J = 7.7 Hz, 2H), 2.42 (s, 3H), 1.71−1.66 (m, 2H), 1.32−1.26 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 191.0, 184.9, 156.6, 155.8, 155.0, 143.2, 138.2, 132.5, 128.8 (2CH), 128.2 (2CH), 124.1, 121.3, 109.8, 108.0, 31.3, 28.7, 27.9, 26.7, 22.4, 14.0, 13.8; HRMS (ESI) m/z calcd for C23H25O4 (M + H)+ 365.1753, found 365.1766.

Ethyl 8-([1,1′-biphenyl]-4-yl)-6-oxo-6H-cyclohepta[b]furan-7-carboxylate (3i). This compound was isolated as a pale yellow solid (21 mg, 75%): mp = 273−276 °C; Rf = 0.4 (EtOAc/Hexane = 2/3); IR (thin film, neat) νmax/cm−1 3031, 2925, 2854, 1730, 1620, 1590, 1539, 1496, 1043, 758; 1H NMR (400 MHz, CDCl3) δ 7.73 (tt, J = 5.3 and 1.9 Hz, 1H), 7.69 (t, J = 1.9 Hz, 1H), 7.67−7.66 (m, 1H), 7.65−7.64 (m, 2H), 7.55 (d, J = 11.9 Hz, 1H), 7.51−7.48 (m, 4H), 7.43−7.39 (m, 1H), 7.15 (d, J = 11.9 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 0.97 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 183.8, 166.6, 146.0, 141.8, 140.2, 137.4, 133.4, 131.3, 129.6, 129.4 (2CH), 128.9 (2CH), 128.8 (2CH), 127.7, 127.2, 127.17 (2CH), 127.11, 126.7, 113.1, 61.3, 13.6; HRMS (ESI) m/z calcd for C24H19O4 (M + H)+ 371.1283, found 371.1287. 6-Oxo-8-phenyl-6H-cyclohepta[b]furan-5,7-diyl)bis(phenylmethanone) (3j). This compound was isolated as a pale yellow solid (15 mg, 76%): mp = 290−293 °C; Rf = 0.4 (EtOAc/Hexane = 2/ 3); IR (thin film, neat) νmax/cm−1 3060, 2924, 2853, 1674, 1597, 1540, 1448, 1286, 1208, 872; 1H NMR (400 MHz, CDCl3) δ 7.94−7.93 (m, 1H), 7.92 (t, J = 4.0 and 2.0 Hz, 2H), 7.71 (m, 1H), 7.69 (t, J = 4.0 Hz, 2H), 7.54 (tt, J = 8.0 and 4.0 Hz, 1H), 7.46−7.40 (m, 3H), 7.32−7.26 (m, 7H), 6.98 (d, J = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 195.8, 194.7, 183.9, 154.0, 146.6, 146.2, 145.3, 138.4, 136.7, 135.8, 133.4, 133.2, 133.2, 131.7, 129.3, 129.2 (2CH), 128.9 (2CH), 128.8 (2CH), 128.5 (2CH), 128.3 (2CH), 128.0 (2CH), 127.7, 113.7; HRMS (ESI) m/z calcd for C29H19O4 (M + H)+ 431.1283, found 431.1267. 8-(Furan-2-yl)-6-oxo-6H-cyclohepta[b]furan-5,7-diyl)bis(phenylmethanone) (3k). This compound was isolated as a pale yellow solid (23 mg, 70%): mp = 285−288 °C; Rf = 0.4 (EtOAc/ Hexane = 2/3); IR (thin film, neat) νmax/cm−1 2923, 2853, 1690, 1674, 1542, 1498, 1261, 835; 1H NMR (400 MHz, CDCl3) δ 7.89−7.86 (m, 4H), 7.83 (d, J = 2.0 Hz, 1H), 7.50 (tt, J = 8.0 and 1.2 Hz, 2H), 7.42− 7.37 (m, 4H), 7.35 (dd, J = 2.0 and 0.8 Hz, 1H), 7.07 (dd, J = 3.6 and 0.6 Hz, 2H), 6.99 (d, J = 2.0 Hz, 1H), 6.47 (dd, J = 2.0 and 1.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 195.4, 184.0, 180.5, 152.1, 146.3, 145.5, 144.6, 143.1, 136.9, 135.7, 133.3, 133.0, 131.2, 129.2 (2CH), 128.7 (2CH), 128.56, 128.54 (2CH), 128.50, 128.4 (2CH), 127.6, 117.5, 113.8, 112.1; HRMS (ESI) m/z calcd for C27H17O5 (M + H)+ 421.1076, found 421.1072. 8-([1,1′-Biphenyl]-4-yl)-6-oxo-6H-cyclohepta[b]furan-5,7-diyl)bis(phenylmethanone) (3l). This compound was isolated as a pale yellow solid (32 mg, 84%): mp = 297−300 °C; Rf = 0.4 (EtOAc/Hexane = 2/ 3); IR (thin film, neat) νmax/cm−1 3059, 2925, 1673, 1597, 1579, 1538, 1494, 1337, 1286, 1006; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.0 Hz, 1H), 7.93−7.92 (m, 2H), 7.73 (d, J = 1.0 Hz, 1H), 7.72−7.71 (m, 2H), 7.57−7.55 (m, 1H), 7.54 (s, 2H), 7.52 (t, J = 1.2 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.44−7.43 (m, 2H), 7.42−7.41 (m, 2H), 7.38 (t, J = 1.2 Hz, 1H), 7.36 (t, J = 2.2 Hz, 1H), 7.35 (t, J = 1.2 Hz, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 6.99 (d, J = 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 195.8, 194.8, 183.9, 154.0, 146.7, 146.2, 145.4, 141.6, 140.0, 138.2, 136.8, 135.8, 133.4, 133.2, 132.1, 131.7, 129.8, 129.8, 129.2 (2CH), 128.9 (2CH), 128.8 (2CH), 128.6 (2CH), 128.3 (2CH), 127.78, 127.74, 127.1 (2CH), 126.6 (2CH), 113.7; HRMS (ESI) m/z calcd for C35H23O4 (M + H)+ 507.1596, found 507.1608. 7-Acetyl-6-phenyl-8H-cyclohepta[b]benzofuran-8-one (3m). This compound was isolated as a pale yellow solid (12 mg, 61%): mp = 201−202 °C; Rf = 0.4 (EtOAc/Hexane = 2/3); IR (thin film, neat) νmax/cm−1 2919, 2852, 1716, 1668, 1635, 1480, 1385, 1284, 819; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 11.9 Hz, 1H), 7.96−7.94 (m, 1H), 7.53−7.50 (m, 3H), 7.49−7.47 (m, 2H), 7.47−7.39 (m, 2H), 7.28 (d, J = 7.4 Hz, 1H), 6.70 (s, 1H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.8, 185.0, 154.5, 149.2, 137.6, 133.8, 129.4 (2CH), 129.3, 129.1, 128.5, 128.4, 128.4 (2CH), 125.8, 124.5, 123.5, 120.1, 116.1, 112.3, 30.9; HRMS (ESI) m/z calcd for C21H15O3 (M + H)+ 315.1021, found 315.1026. 7-Benzoyl-6-phenyl-8H-cyclohepta[b]benzofuran-8-one (3n). This compound was isolated as a pale yellow solid (15 mg, 65%): mp = 207−210 °C; Rf = 0.4 (EtOAc/Hexane = 2/3); IR (thin film, neat) νmax/cm−1 2922, 2852, 1709, 1668, 1635, 1557, 1480, 1446,

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ASSOCIATED CONTENT

S Supporting Information *

Figures giving 1H and 13C NMR of all new compounds, some physicochemical data and figures, tables, and CIF files giving J

DOI: 10.1021/acs.joc.5b00226 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

(8) Dhiman, S.; Ramasastry, S. S. V. Org. Biomol. Chem. 2013, 11, 4299. (9) 2,3′-Bifurans traditionally have been synthesized by employing typical Pd-mediated coupling strategy. Few miscellaneous methods, though not general in nature, are reported. For example, see: (a) Pennanen, S. I. J. Heterocycl. Chem. 1977, 14, 745. (b) Liu, Z.; Yu, W.; Yang, L.; Liu, Z.-L. Tetrahedron Lett. 2007, 48, 5321. (c) Kumar, T.; Mobin, S. M.; Namboothiri, I. N. N. Tetrahedron 2013, 69, 4964. (10) For frondosin B, see: (a) Patil, A. D.; Freyer, A. J.; Kilmer, L.; Offen, P.; Carte, B.; Jurewicz, A. J.; Johnson, R. K. Tetrahedron 1997, 53, 5047. For liphagal, see: (b) Marion, F.; Williams, D. E.; Patrick, B. O.; Hollander, I.; Mallon, R.; Kim, S. C.; Roll, D. M.; Feldberg, L.; Soest, R. V.; Andersen, R. J. Org. Lett. 2006, 8, 321. For salvixalapoxide, see: (c) Esquivel, B.; Tello, R.; Sanchez, A. A. J. Nat. Prod. 2005, 68, 787. For languidulane, see: (d) Maldonado, E.; Ortega, A. Phytochemistry 1997, 45, 1461. For spiniferin-2, see: (e) Fontana, A.; Trivellone, E.; Mollo, E.; Cimino, G. J. Nat. Prod. 1994, 57, 510. For gnididione, see: (f) Jacobi, P. A.; Selnick, H. G. J. Org. Chem. 1990, 55, 202. (11) Test solutions containing Zn2+, Mg2+, Ni2+, Cu2+, Hg2+, Sn2+, Co2+, In2+, Sn2+, Cd2+, Cr2+, Fe2+ were prepared by using their halides, and Pb2+ solution was prepared by using its nitrate. (12) Sahoo, S. K.; Sharma, D.; Bera, R. K.; Crisponi, G.; Callan, J. F. Chem. Soc. Rev. 2012, 41, 7195.

single crystal X-ray diffraction analysis data of compound 3j. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.5b00226.

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Corresponding Author

*Tel: (+91) 172 2293169. Fax: (+91) 172 2240266. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Department of Science and Technology (DST), New Delhi for financial support through Fast Track Scheme (SR/FT/CS-156/2011) and Indian Institute of Science Education and Research (IISER) Mohali for funding. We thank NMR and X-ray facilities of IISER-Mohali. We thank DCS colleagues for their help in recording and analyzing UV− vis and fluorescence data. R.S. thanks IISER-Mohali for a research fellowship.

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REFERENCES

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DOI: 10.1021/acs.joc.5b00226 J. Org. Chem. XXXX, XXX, XXX−XXX